Key points

Introduction

Bone sarcomas and soft-tissue sarcomas (STS) encompass a heterogeneous group of human cancers that derive from the embryonic mesoderm. The diversity of sarcomas, with respect to histology, natural history, therapeutic sensitivities, and metastatic potential, stems in part from the diversity of mesodermic tissue, which includes bone, cartilage, adipose, muscle, vasculature, and hematopoietic. In the orthopedic literature, sarcomas tend to be broadly categorized as either of bone or soft tissue in origin. However, recent genomic and molecular discoveries ( Table 1 ) have enabled us to reclassify these tumors and expand our therapeutic breadth to include optimized (and often personalized) cytotoxic chemotherapeutic regimens, radiopharmaceuticals, oncolytic viruses, immune-modulating therapies, and—the focus of this review—targeted chemotherapeutic agents. Although the mainstay of therapy for localized sarcoma remains surgical resection, neoadjuvant and adjuvant chemotherapy, and radiation, play an essential role in both local and systemic control.

The effect of chemotherapy has been most profound in the management of localized primary bone sarcomas, including osteosarcoma and Ewing sarcoma (ES). Link and colleagues conducted one of the first randomized controlled trials showing the benefit of adjuvant chemotherapy in patients with localized osteosarcoma. At 2 years, patients who received chemotherapy had improved relapse-free survival of 66% compared with 17%; however, because of the short duration, they were unable to show an improvement in overall survival. Similar results were demonstrated by Eilber and colleagues in 1987, recently validated with long-term follow-up showing a durable improvement in overall survival with adjuvant chemotherapy. In the decades following, clinical research has focused primarily on optimizing adjuvant cytotoxic regimens, including the initiation of neoadjuvant chemotherapy. Current National Comprehensive Cancer Network guidelines recommend 1 of 4 first-line regimens including cisplatin/doxorubicin, high-dose methotrexate/cisplatin/doxorubicin with or without ifosfamide, or ifosfamide/cisplatin/epirubicin. Despite the relative success in the treatment of nonmetastatic osteosarcoma, progression-free survival (PFS) and overall survival in metastatic osteosarcoma remains poor and an area that demands innovation.

Similarly to osteosarcoma, ES of bone has a predilection for adolescents and a tendency to have subclinical micrometastases at the time of presentation. More specifically, analysis of a large cohort of ES patients demonstrated that 18.4% presented with metastatic disease. The addition of chemotherapy to the treatment algorithm in ES similarly revolutionized treatment outcomes in localized ES. After further studies optimizing sequencing and timing of the chemotherapeutic agents, current treatment regimens involve neoadjuvant chemotherapy with a combination of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, followed by surgery and adjuvant chemotherapy with or without radiation. This treatment strategy results in a 5-year relapse-free and overall survival of 52% to 78% in localized ES, with outcomes closely tied to the histologic response to neoadjuvant therapy and the presence of metastatic disease. Unfortunately, as with osteosarcoma, despite the optimization of cytotoxic regimens the 10-year overall survival in patients with metastatic ES is only 27% to 39%.

Chondrosarcoma, a heterogeneous group of malignant cartilaginous tumors most commonly seen in the adult population, has traditionally been considered both chemoresistant and radiation resistant. At present, surgical resection is the primary treatment modality; however, in patients with high-grade/metastatic disease or certain histologic subtypes adjuvant therapy may be considered, underscoring the importance of novel targeted therapies in high-risk patients. STS are traditionally considered to be chemoresistant tumors, and therapy relies heavily on surgical resection and, if a high-grade lesion, localized radiation to improve local control. The 5-year survival of nonmetastatic high-grade STS of the extremity is approximately 70%, with local recurrence having the greatest effect on survival. However, in the setting of metastatic high-grade extremity STS, survival is dismal, with 3-year survival rates less than 20%. There are, however, certain groups of patients that do benefit from systemic chemotherapy. Meta-analysis of doxorubicin-based adjuvant chemotherapy has demonstrated an improvement in time to recurrence and overall recurrence-free survival, an effect that was more significant in extremity STS. Unfortunately, this improvement in recurrence rate did not translate into an increased overall survival. Additional studies and a recent meta-analysis have supported the use of high-dose ifosfamide as an additional first-line agent.

Further evaluation of specific histologic subtypes has shown a small number of STS that are particularly responsive to adjuvant chemotherapy. The ANGIOTAX study, a phase II clinical trial investigating the effect of paclitaxel in patients with metastatic or unresectable angiosarcoma, demonstrated a modest clinical benefit. With the addition of paclitaxel the PFS at 2 months was 74%, however, this was not a durable response with only a 24% PFS at 6 months and an overall 18-month survival of 21%. In patients with liposarcoma, doxorubicin remains the agent of choice; interestingly the myxoid liposarcoma variant is particularly sensitive to cytotoxic regimens. Finally, historical data show that synovial cell sarcoma is sensitive to high-dose ifosfamide therapy, a finding that was further supported by a large retrospective analysis of patients with STS treated in the European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group. A common constraint with the aforementioned regimens is discontinuation secondary to dosing limitations with long-term therapy, possibly leading to relapse with poor outcomes. In a 2011 review by Patrikidou and colleagues, several key limitations with the use of adjuvant chemotherapy in STS were discussed. Specifically, the lack of homogenous subtype studies attributable to the rarity of STS and the need for subtype targeted therapy was highlighted.

In conclusion, current systemic treatment strategies are marginally effective for most bone sarcomas and STS, underscoring the need for more effective and individualized regimens. Table 2 lists several relevant completed and ongoing clinical trials and studies.

Introduction

Bone sarcomas and soft-tissue sarcomas (STS) encompass a heterogeneous group of human cancers that derive from the embryonic mesoderm. The diversity of sarcomas, with respect to histology, natural history, therapeutic sensitivities, and metastatic potential, stems in part from the diversity of mesodermic tissue, which includes bone, cartilage, adipose, muscle, vasculature, and hematopoietic. In the orthopedic literature, sarcomas tend to be broadly categorized as either of bone or soft tissue in origin. However, recent genomic and molecular discoveries ( Table 1 ) have enabled us to reclassify these tumors and expand our therapeutic breadth to include optimized (and often personalized) cytotoxic chemotherapeutic regimens, radiopharmaceuticals, oncolytic viruses, immune-modulating therapies, and—the focus of this review—targeted chemotherapeutic agents. Although the mainstay of therapy for localized sarcoma remains surgical resection, neoadjuvant and adjuvant chemotherapy, and radiation, play an essential role in both local and systemic control.

The effect of chemotherapy has been most profound in the management of localized primary bone sarcomas, including osteosarcoma and Ewing sarcoma (ES). Link and colleagues conducted one of the first randomized controlled trials showing the benefit of adjuvant chemotherapy in patients with localized osteosarcoma. At 2 years, patients who received chemotherapy had improved relapse-free survival of 66% compared with 17%; however, because of the short duration, they were unable to show an improvement in overall survival. Similar results were demonstrated by Eilber and colleagues in 1987, recently validated with long-term follow-up showing a durable improvement in overall survival with adjuvant chemotherapy. In the decades following, clinical research has focused primarily on optimizing adjuvant cytotoxic regimens, including the initiation of neoadjuvant chemotherapy. Current National Comprehensive Cancer Network guidelines recommend 1 of 4 first-line regimens including cisplatin/doxorubicin, high-dose methotrexate/cisplatin/doxorubicin with or without ifosfamide, or ifosfamide/cisplatin/epirubicin. Despite the relative success in the treatment of nonmetastatic osteosarcoma, progression-free survival (PFS) and overall survival in metastatic osteosarcoma remains poor and an area that demands innovation.

Similarly to osteosarcoma, ES of bone has a predilection for adolescents and a tendency to have subclinical micrometastases at the time of presentation. More specifically, analysis of a large cohort of ES patients demonstrated that 18.4% presented with metastatic disease. The addition of chemotherapy to the treatment algorithm in ES similarly revolutionized treatment outcomes in localized ES. After further studies optimizing sequencing and timing of the chemotherapeutic agents, current treatment regimens involve neoadjuvant chemotherapy with a combination of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, followed by surgery and adjuvant chemotherapy with or without radiation. This treatment strategy results in a 5-year relapse-free and overall survival of 52% to 78% in localized ES, with outcomes closely tied to the histologic response to neoadjuvant therapy and the presence of metastatic disease. Unfortunately, as with osteosarcoma, despite the optimization of cytotoxic regimens the 10-year overall survival in patients with metastatic ES is only 27% to 39%.

Chondrosarcoma, a heterogeneous group of malignant cartilaginous tumors most commonly seen in the adult population, has traditionally been considered both chemoresistant and radiation resistant. At present, surgical resection is the primary treatment modality; however, in patients with high-grade/metastatic disease or certain histologic subtypes adjuvant therapy may be considered, underscoring the importance of novel targeted therapies in high-risk patients. STS are traditionally considered to be chemoresistant tumors, and therapy relies heavily on surgical resection and, if a high-grade lesion, localized radiation to improve local control. The 5-year survival of nonmetastatic high-grade STS of the extremity is approximately 70%, with local recurrence having the greatest effect on survival. However, in the setting of metastatic high-grade extremity STS, survival is dismal, with 3-year survival rates less than 20%. There are, however, certain groups of patients that do benefit from systemic chemotherapy. Meta-analysis of doxorubicin-based adjuvant chemotherapy has demonstrated an improvement in time to recurrence and overall recurrence-free survival, an effect that was more significant in extremity STS. Unfortunately, this improvement in recurrence rate did not translate into an increased overall survival. Additional studies and a recent meta-analysis have supported the use of high-dose ifosfamide as an additional first-line agent.

Further evaluation of specific histologic subtypes has shown a small number of STS that are particularly responsive to adjuvant chemotherapy. The ANGIOTAX study, a phase II clinical trial investigating the effect of paclitaxel in patients with metastatic or unresectable angiosarcoma, demonstrated a modest clinical benefit. With the addition of paclitaxel the PFS at 2 months was 74%, however, this was not a durable response with only a 24% PFS at 6 months and an overall 18-month survival of 21%. In patients with liposarcoma, doxorubicin remains the agent of choice; interestingly the myxoid liposarcoma variant is particularly sensitive to cytotoxic regimens. Finally, historical data show that synovial cell sarcoma is sensitive to high-dose ifosfamide therapy, a finding that was further supported by a large retrospective analysis of patients with STS treated in the European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group. A common constraint with the aforementioned regimens is discontinuation secondary to dosing limitations with long-term therapy, possibly leading to relapse with poor outcomes. In a 2011 review by Patrikidou and colleagues, several key limitations with the use of adjuvant chemotherapy in STS were discussed. Specifically, the lack of homogenous subtype studies attributable to the rarity of STS and the need for subtype targeted therapy was highlighted.

In conclusion, current systemic treatment strategies are marginally effective for most bone sarcomas and STS, underscoring the need for more effective and individualized regimens. Table 2 lists several relevant completed and ongoing clinical trials and studies.

Table 2

Current and recently completed clinical trials

Trial/Reference	Date	Phase	Tumor	Mechanism of Action/Target	Agent(s) Tested	Route/Frequency	Number Treated	Results
NCT01524926 /(Schöffski, 2012)	—	II	AKT and/or MET altered tumors to include alveolar soft-part sarcoma, clear cell sarcoma, and alveolar rhabdomyosarcoma (≥15 y old)	Alk/MET	Crizotinib	PO/daily	582 (estimate)	Recruiting
NCT00093080 (Chawla et al, 2012)	2004	II	Metastatic/unresectable soft-tissue or bone sarcoma	mTOR inhibitor	Ridaforolimus	IV/daily	212	28.8% achieved clinical benefit response (CR, PR, or SD for >16 wk)
(Yoo et al, 2013)	—	II	Metastatic or recurrent bone and STS after the failure of anthracycline- and ifosfamide-containing regimens	mTOR inhibition	Everolimus	PO/daily	38	28.9% reached 16-wk PFS. Median PFS was 1.9 mo and median OS was 5.8 mo
NCT01614795 (Wagner, 2015, #8372)	2012	II	STS (1–30 y old)	IGF-1R + mTOR	Cixutumumab + Temsirolimus	IV/weekly	43	No responses. 16% PF at 12 wk
NCT01016015 (Schwartz et al, 2013)	2009	II	STS (1–30 y old)	IGF-1R + mTOR	Cixutumumab + Temsirolimus	IV/weekly	174	Combination therapy with clinical activity. 39% were PF at 12 wk. IGF-1R expression not predictive of outcome
NCT00831844 (Weigel, 2014)	2009	II	Solid tumors (7–30 y old)	IGF-1R	Cixutumumab	IV/weekly	114	Limited activity noted. 4.4% with PR. 12.3% with SD
NCT00563680 (Tap et al, 2012)	2007–2012	II	Ewing family tumors, DSRCTs (≥16 y old)	IGF-1R monoclonal antibody	Ganitumab	—	38	ORR was primary end point and seen in 6% of patients. CBR (seen in 17% of patients) and safety were secondary end points. 49% had SD. 63% experienced adverse events
NCT00642941 (Pappo et al, 2014)	2007–2010	II	Recurrent/refractory rhabdomyosarcoma, osteosarcoma, and synovial sarcoma (≥2 y old)	IGF-1R monoclonal antibody	R1507	IV/weekly	228	ORR was 2.5%. Partial responses were seen in 4 patients. 4 patients had >50% reduction in tumor size that lasted <4 wk. Median PFS was 5.7 wk. Median OS was 11 mo
NCT00385203 (Judson et al, 2014)	2006–2009	II	GIST + STS progressing on imatinib/sunitinib	VEGF	Cediranib	Daily	34	Some activity noted by 18 FDG-PET in 5 patients, but no statistical reduction in SUV max across the cohort. 4 of 6 patients with ASPS saw confirmed and durable partial responses
NCT00942877 (Kummar et al, 2013)	2009	II	ASPS	VEGFR inhibitor	Cediranib	PO/daily	43	Partial response seen in 35% of patients. SD seen in 60%. Disease control rate of 84% at 24 wk
NCT00288015 (Agulnik et al, 2013)	2006	II	Angiosarcoma and epithelioid hemangioendotheliomas	VEGF antibody	Bevacizumab	IV	32	Therapy was well tolerated in 15 patients with SD at 26 wk
NCT00070109 (Baruchel et al, 2012)	2008–2013	II	Recurrent rhabdomyosarcoma, ES, and nonrhabdomyosarcoma STS	Unknown, suspect superoxide-induced apoptosis	Trabectedin	IV/every 3 wk	50	1 RMS patient had PR; 1 with RMS, 1 with SCS, and 1 with ES had SD at 2, 3, and 15 cycles
NCT01189253 (Butrynski, 2015), EORTC	2011	III	Advanced/metastatic-related sarcomas	Unknown, suspect superoxide-induced apoptosis	Trabectedin vs doxorubicin-based chemotherapy (DXCT)	IV/every 3 wk	121	PFS and survival curves with no significant differences between arms. Response rate was higher in DXCT arm
(Cesne et al, 2013)	—	II	Recurrent/advanced STS	Unknown, suspect superoxide-induced apoptosis	Trabectedin	—	350	Pooled analysis of 5 phase II studies. RR (10.1% in younger, 9.6% in older), PFS (2.5 vs 3.7 mo), and OS (13 vs 14 mo) did not differ among young and elderly cohorts
NCT01303094 (Le Cesne et al, 2015, #71639)	2011	II	Advanced STS (≥18 y old)	Unknown, suspect superoxide-induced apoptosis	Trabectedin	IV/every 3 wk	178	91 patients (51%) had not progressed. Of these 53 were randomly assigned to continuation (C) vs interruption (I). PFS at 6 mo was 51.9% in the C group and 23.1% in the I group
NCT00928525 (Grignani, 2011)	—	II	Chondrosarcoma	COL1A1-PDGFB	Imatinib	IM	26	PFS at 4 mo was 35%, median OS was 11 mo. No long-lasting disease-free progression or clinical benefit was observed. Temporary dose reduction required in 60%
(Ugurel et al, 2014)	—	II	Dermatofibrosarcoma protuberans	COL1A1-PDGFB	Imatinib	Daily	16	Primary end point was response with secondary end points as safety, tumor relapse, and response biomarkers. Median therapy duration was 3.1 mo. Median tumor shrinkage was 31.5%. CR of 7.1%, PR of 50%, 35.7% SD, and 7.1% PD was seen. Neoadjuvant use was efficacious and well tolerated
(Sugiura et al, 2010)	—	II	Metastatic unresectable or refractory KIT+/PDGFR+ sarcoma (12–75 y old)	Multitargeted tyrosine kinase inhibitor	Imatinib	Daily	22	1 PR (4.5%). 50% PFS at 61 d
NCT01209598 (Dickson, 2013)	2010–current	II	CDK-4-amplified liposarcoma (≥18 y old)	CDK4/CDK6 inhibitor	PD0332991	PO/daily	29	At 12 wk, PFS was 66%, exceeding the 40% needed to consider the study positive
NCT00023998 (Ebb, 2012)	2001–current	II	HER2+ osteosarcoma	Monoclonal antibody that interferes with HER2/neu receptor	Trastuzumab + chemotherapy	—	96 received chemotherapy (41 of these were HER+ and received trastuzumab)	Outcomes were poor. No significant difference between HER2− and HER2+ patients (EFS at 30 mo of 32% in both groups, OS 50% and 59%, respectively)
NCT00217620 (Von Mehren, Demetri, 2012)	—	II	STS	Multitargeted tyrosine kinase inhibitor	Sorafenib	BID	37	No responses in any of the cohorts. Median PFS was 3 mo. Median OS was 17 mo
NCT00889057 (Grignani et al, 2012)	2008–2011	II	Osteosarcoma (15–75 y old)	Multitargeted tyrosine kinase inhibitor	Sorafenib	BID	35	PFS at 4 mo was 46%. Median PFS was 4 mo. Median OS of 7 mo. CBR 29%. PR in 8%. Minor response in 6%. SD in 34%. PR/SD >6 mo in 17%
NCT01804374 /SERIO (Aglietta, 2015)	2011–2014	II	Unresectable advanced and metastatic osteosarcoma (≥18 y old)	Multitargeted tyrosine kinase inhibitor/mTOR	Sorafenib + Everolimus	Daily	38	Dose reduction/interruptions were required in 66%. 6-mo PFS was 45%, shy of the 50% threshold to call the study positive
NCT00297258 (Sleijfer et al, 2009)	2005–2012	II	STS	Multitargeted tyrosine kinase inhibitor	Pazopanib	PO/daily	148	Primary end point of PFS at 12 wk and secondary end points of response, safety, and OS were reached in leiomyosarcoma, synovial sarcoma, and other cohorts. End points were not reached in the adipocytic STS cohort

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